The 1,3-oxathiolane ring is a common feature of many useful compounds, including those with medicinal value. Cevimeline is a cholinergic agonist that binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts. Cevimeline is marketed in the USA as Evoxac®, and is indicated for the treatment of symptoms of dry mouth in patients with Sjögren's Syndrome. Cevimeline is marketed as the hydrochloride hemihydrate salt with the chemical name cis-2-methylspiro(1,3-oxathiolane-5,3′-quinuclidine) hydrochloride hemihydrate.
U.S. Pat. No. 4,855,290 describes a process for the preparation of 2-methylspiro(1,3-oxathiolane-5,3′-quinuclidine) (1), which comprises the preparation of the epoxide of 3-methylenequinuclidine, which is subsequently reacted with hydrogen sulfide to produce 3-hydroxy-3-mercaptomethylquinuclidine and is condensed with acetaldehyde in the presence of a Lewis acid (e.g. boron trifluoride etherate) to provide 2-methylspiro(1,3-oxathiolane-5,3′-quinuclidine).
U.S. Pat. No. 5,571,918 describes a method for producing 2-methylspiro(1,3-oxathiolane-5,3′-quinuclidine), which comprises reacting 3-hydroxy-3-mercaptomethylquinuclidine or a salt thereof and a carbonyl compound in the presence of a catalyst to produce the cis-form of 2-methylspiro(1,3-oxathiolane-5,3′-quinuclidine) or a salt thereof.
U.S. Pat. No. 4,861,886 describes a method for isomerization of the trans-form of 2-methylspiro(1,3-oxathiolane-5,3′-quinuclidine) or acid addition salts thereof to cis-form 2-methylspiro(1,3-oxathiolane-5,3′-quinuclidine) or acid addition salts thereof in the presence of at least one acid catalyst selected from the group consisting of an organic sulfonic acid, a halide functioning as a Lewis acid, and sulfonic acid.
U.S. Pat. No. 8,080,663 describes a process for the preparation of 2-methylspiro(1,3-oxathiolane-5,3′-quinuclidine) (1), which comprises the preparation of the epoxide of 3-methylenequinuclidine, which is subsequently reacted with thioacetic acid to give the thioacetic acid salt of 3-hydroxy-3-acetoxymercaptomethylquinuclidine, which upon acid or base hydrolysis is converted to 3-hydroxy-3-mercaptomethylquinuclidine, which is subsequently condensed with acetal to provide a mixture of cisitrans 2-methylspiro(1,3-oxathiolane-5,3′-quinuclidine).
WO publication 2011049155 discloses a process for the preparation of a cis-type 2-alkylspiro(1,3-oxathiolane-5,3′-quinuclidine) hydrochloric acid salt, which comprises reacting p-nitrobenzoic acid with a cisitrans isomer mixture of a 2-alkylspiro(1,3-oxathiolane-5,3′-quinuclidine), resolving the resulting product to provide a cis-type 2-alkylspiro(1,3-oxathiolane-5,3′) p-nitrobenzoic acid salt, and converting the p-nitrobenzoic acid salt into the hydrochloric acid salt.